The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are significant causes of morbidity with recent estimates suggesting there are more than 3 million Americans with IBD with very significant financial burden to the US economy. More than 200 genetic loci that increase susceptibility to IBD have been identified with the anticipation that an understanding of the molecular architecture of IBD will lead to improved outcomes for patients. However, there are significant challenges remaining to achieve this and this proposal seeks to address some of these key issues. 1) The majority of advances have been made in European ancestry populations and we aim to continue our efforts to recruit and study non-European populations to extend the benefits of these advances to all parts of society. 2) We will address unmet medical needs by focusing on genetic discovery in two areas: peri-anal fistulizing CD is associated with poor quality of life, significant morbidity, and poor response to treatment; and non-response to anti-TNF therapy which happens in the majority of subjects with IBD. This latter phenotype is increasingly important to define as new therapeutic options become available for treating IBD. 3) Many of the IBD associated loci fall in intergenic ('junk' DNA) regions and their functional consequences remain unclear. Using innovative genomic approaches together with state-of-the-art bioinformatics strategies we propose to identify the processes that are influenced by the susceptibility loci we have identified. 4) And finally we will extend our previous observations that Paneth cell phenotypes are an important readout of gene-environment interactions, as well as an important clinical biomarker, in CD to populations from a variety of ethnicities and geographical locations. Collectively, these approaches will shed additional insights into the underlying causes of IBD as well as identify additional biomarkers for use in clinical practice and highlight novel potential therapeutic pathways for IBD.